Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
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Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge. / Emmett, Matthew J.; Lim, Hee-Woong; Jager, Jennifer; Richter, Hannah J.; Adlanmerini, Marine; Peed, Lindsey C.; Briggs, Erika R.; Steger, David J.; Ma, Tao; Sims, Carrie A.; Baur, Joseph A.; Pei, Liming; Won, Kyoung-Jae; Seale, Patrick; Gerhart-Hines, Zachary; Lazar, Mitchell A.
I: Nature Genetics, Bind 546, Nr. 7659, 2017, s. 544-448.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
AU - Emmett, Matthew J.
AU - Lim, Hee-Woong
AU - Jager, Jennifer
AU - Richter, Hannah J.
AU - Adlanmerini, Marine
AU - Peed, Lindsey C.
AU - Briggs, Erika R.
AU - Steger, David J.
AU - Ma, Tao
AU - Sims, Carrie A.
AU - Baur, Joseph A.
AU - Pei, Liming
AU - Won, Kyoung-Jae
AU - Seale, Patrick
AU - Gerhart-Hines, Zachary
AU - Lazar, Mitchell A.
PY - 2017
Y1 - 2017
N2 - Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.
AB - Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.
U2 - 10.1038/nature22819
DO - 10.1038/nature22819
M3 - Journal article
C2 - 28614293
VL - 546
SP - 544
EP - 448
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 7659
ER -
ID: 182539799